The indole nucleus is the most common heterocycle found in nature. Many indole-containing compounds possess potent biological activity, which has earned this structural core the description of “privileged” in therapeutic discovery. Beginning with Möhlau and Fischer, the indole has captured the attention of the chemical community since the late 19th century. Historically, the most common method is the Fischer indole synthesis, but this reaction can be limited in scope due to the stability of the hydrazine component, preparation of aryl hydrazines, and strong acidic conditions. The Bischler-Möhlau synthesis of 2-aryl indoles usually requires high temperatures that can lead to low yields and regiochemistry problems.
In the development of new strategies to access this key heterocycle, modern chemical research has focused on transition metal-catalyzed approaches (Scheme 1a-d, prior art). For example, the Larock indole synthesis and Suzuki coupling strategies have enabled the synthesis of previously inaccessible indole scaffolds, with more recent work by Gaunt describing a copper-catalyzed arylation of indoles. While greatly expanding access to diverse indole structures, these methods use metal catalysts which can contaminate the desired products with difficult to remove toxic-metal impurities or require starting materials such as alkynes and prefunctionalized indoles.